It has been found that host responses to pathogens can be mediated via highly coordinated mechanisms involving both innate and adaptive limbs of the immune system. The innate immune system utilizes germline-encoded pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) that are distinct and unique to the pathogen. PRRs encompass a broad range of molecules that are secreted into the extracellular environment (e.g., collectins, ficolins, pentraxins, alarmins), exist in the cytosol (e.g., retinoic acid-inducible gene I-like receptors, and the nucleotide-binding domain and leucine-rich repeatcontaining receptors), or are present on membranes.
Important among the transmembrane PRRs are the Toll-like receptors (TLR5), which are either expressed on the plasma membrane or in the endolysosomal compartments. At least 10 functional TLRs are encoded in the human genome, each with an extracellular domain having leucine-rich repeats (LRR) and a cytosolic domain called the Toll/IL-1 receptor (TIR) domain. The ligands for these receptors are highly conserved microbial molecules such as lipopolysaccharides (LPS) (recognized by TLR4), lipopeptides (TLR2 in combination with TLR1 or TLR6), flagellin (TLR5), single stranded RNA (TLR7 and TLR8), double stranded RNA (TLR3), CpG motif-containing DNA (recognized by TLR9), and profilin present on uropathogenic bacteria (TLR11). TLR1, -2, -4, -5, and -6 recognize extracellular stimuli, while TLR3, -7, -8 and -9 function within the endolysosomal compartment. The activation of TLRs by their cognate ligands leads to production of inflammatory cytokines, and up-regulation of major histocompatibility complex (MHC) molecules and co-stimulatory signals in antigen-presenting cells as well as activating natural killer (NK) cells (innate immune response), which lead to the priming and amplification of T-, and B-cell effector functions (adaptive immune responses).
In many instances, a TLR agonist may agonize multiple TLRs. However, it may be advantageous to selectively target only one TLR, such as TLR8, for therapeutic, diagnostic, or other purposes.